CN1308611A

CN1308611A - Novel antihistamine piperidine derivatives and intermediates for their preparation

Info

Publication number: CN1308611A
Application number: CN99808132A
Authority: CN
Inventors: 蒂莫西·A·艾尔斯; 保罗·W·布朗
Original assignee: Aventis Pharmaceuticals Inc
Current assignee: Auin Thurber Holding Co; Auin Thurber Ltd By Share Ltd; Aventis Saab LLC
Priority date: 1998-07-02
Filing date: 1999-06-17
Publication date: 2001-08-15
Anticipated expiration: 2019-06-17
Also published as: IL171479A; ZA200007034B; KR20060035816A; KR100682447B1; CN1246312C; IL171062A; PT1091938E; BR9911794A; KR20010053324A; IL171063A; ATE485271T1; EP1091938B1; AU4574699A; ES2354968T3; HK1034065A1; DE69942876D1; TW533197B; NO20006694L; CA2336380A1; CN101311165B

Abstract

The present invention relates to novel piperidine derivatives of formula wherein R is₁Is H or C₁～C₆Alkyl radical, C thereof₁～C₆The alkyl moiety being straight or branched, R₂is-COOH or-COO alkyl, the alkyl part of which has 1 to 6 carbon atoms and is straight-chain or branched, or a stereoisomer thereof or a pharmaceutically acceptable acid addition salt thereof.

Description

New anti-histamine piperidine derivatives and prepare its intermediate

Background of invention

The present invention relates to molecular formula as the new piperidine derivative of (I) and preparation method thereof,

Wherein

R ₁Be H or C ₁～C ₆Alkyl, its C ₁～C ₆Moieties is a straight or branched;

R ₂Be-COOH or-the COO alkyl, its moieties has 1 to 6 carbon atom, is straight or branched; Or its steric isomer or the acceptable acid-adducting salt of pharmacy (acid addition salts).

Terfenadine, α-[4-(1,1-diformazan ethyl) phenyl]-4-(hydroxyl diphenyl-methyl)-1-piperidine butanol is a known antihistaminic, on sale on market at present, its trade(brand)name is Seldane ^, recommended dose is 60mg, twice of every day is (referring to Physician ' s DeskReference, 52nd Edition, 1998, pp.1238～1244, Medical EconomicsData, a division of Medical Economics Company, Inc.Montvale, NewJersey).The U.S.P.No.3 that terfenadine was authorized on April 15th, 1975 is disclosed in 878,217.Sorken and Heel have carried out summarizing [Drugs29,34～56 (1985)] to the pharmacokinetic property and the curative effect of terfenadine.

(99%) first pass metabolism becomes two primary metabolites (fexofenadine) and an inactivation to terfenadine through widely removes the alkyl metabolite.Fexofenadine is called 4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino again] butyl]-α, alpha-alpha-dimethyl-toluylic acid, as a kind of antihistaminic with Orally active, the U.S.P.No.4 that authorizes on March 3rd, 1981, open in 254,129.It is on sale on market at present, and its trade(brand)name is Allegra ^(referring to Physician ' s Desk Reference, 52nd Edition, 1998, pp.1189～1190, Medical Economics Data, a division of Medical Economics Company, Inc.Montvale, New Jersey).

Summary of the invention

One of purpose of the present invention provides the molecular formula that the is used for the treatment of allergic disorder new piperidine derivative as (I), further the purpose new intermediate that provides the method for preparing said derivative and be used to prepare these derivatives.

In addition, one of purpose of the present invention provides a kind of method of treatment allergic disorder patient, comprise give described 10 patients (said 10 patient) effectively the molecular formula of antianaphylaxis amount as the compound of (I).

In addition, one of purpose of the present invention provides a kind of composition, but comprises the compound of the molecular formula of amount of analysis as (I), and this compound is with one or more pharmaceutically acceptable carriers or mixed with excipients or combine.

Another object of the present invention provides the novel method that preparation is used for the intermediate of synthetic fexofenadine and related compound.

According to the further investigation to specification sheets and claims, further aim of the present invention and advantage will become clear to those skilled in the art.

Detailed description of the present invention

Molecular formula can be prepared by technology and the method that those of ordinary skills were familiar with and knew as the compound of (I).

The straight or branched alkyl that contains 1 to 6 carbon atom used herein refers to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the amyl group of the tertiary butyl and straight chain and side chain and hexyl.

Molecular formula can form pharmacologically acceptable salts as the piperidine derivative of (I).The acceptable acid-adducting salt of the pharmacy of the compound that the present invention relates to is those and any suitable inorganic or salt that organic acid became.Suitable mineral acid is, for example, and hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid.Suitable organic acid comprises carboxylic acid such as acetic acid, propionic acid, oxyacetic acid, lactic acid, pyruvic acid, propanedioic acid, succsinic acid, FUMARIC ACID TECH GRADE, oxysuccinic acid, tartrate, citric acid, cyclohexane sulfamic acid, xitix, maleic acid, hydroxymaleic acid and dihydroxymaleic acid, phenylformic acid, toluylic acid, 4-benzaminic acid; 4-hydroxy-benzoic acid, anthranilic acid, styracin, Whitfield's ointment, 4-aminosallcylic acid; 2-phenoxy benzoic acid, 2-acetylbenzoic acid, phenylglycollic acid; sulfonic acid such as methylsulfonic acid, ethyl sulfonic acid and beta-hydroxy ethyl sulfonic acid.Molecular formula as above compound and inorganic or organic bases form non-toxic salts be also included within the scope of the present invention, comprise, for example, with the salt of basic metal such as sodium, potassium and lithium formation, with the salt of alkaline-earth metal such as calcium and magnesium formation, with the salt of group IIIA light metal such as aluminium formation, with organic amine as primary, the second month in a season and tertiary amine, as cyclo-hexylamine, ethamine, pyridine, the salt that methyl amido ethanol and piperazine form.These salt can prepare by traditional method, for example, molecular formula are handled with suitable acid or alkali as the piperidine derivative of (I).

Schema A has listed the new preparation method of molecular formula as the piperidine derivative of (I).In schema A, R ₁And R ₂Be C ₁～C ₆Alkyl, its C ₁～C ₆Moieties is a straight or branched; R ₃Be H or C ₁～C ₆Alkyl, its C ₁～C ₆Moieties is a straight or branched; X is Cl, Br or I.

Schema A

Schema A (continuing)

Schema A provides preparation molecular formula synthetic method as the compound of (I).

In steps A, phenylacetyl halogen (1), wherein X is Cl, Br or I, with the reaction of N-O-dimethyl oxammonium hydrochloride, generates N-methoxyl group-N-methylbenzene ethanamide (2).

For example, suitable phenylacetyl halogen (1) contacts in appropriate solvent such as toluene with the salt of wormwood of molar excess.Suitable phenylacetyl halogen comprises phenyllacetyl chloride, phenylacetyl bromine or phenylacetyl iodine.Preferred phenylacetyl halogen is phenyllacetyl chloride.Then add the equimolar N-O-dimethyl oxammonium hydrochloride that is dissolved in the water.Reaction mixture stirred in 0 ℃ to 66 ℃ temperature range 1 to 24 hour.Preferred churning time is 3 hours.Preferred temperature is 25 ℃.N-methoxyl group-N-methyl-phenylacetamide (2) reclaims from responding layer by extracting method known in the art.

In step B; N-methoxyl group-N-methyl-phenylacetamide (2) is under the Friedel-Crafts condition; through the butyryl halogen acidylate that the following 4-halogen of suitable molecular formula replaces, the mixture of ω-halo-α-ketone group-phenylacetamide (3) that the position replaced between the generation contraposition reached

Wherein each X represents Cl, Br or I independently.Surprisingly, para-isomeride is easy to be separated through the crystallization described in the following step C.

For example, in step B, N-methoxyl group-N-methylbenzene ethanamide (2) contacts under general Friedel-Crafts acylation condition with suitable Lewis acid with the butyryl halogen that suitable 4-halogen replaces.The example of the butyryl halogen that suitable 4-halogen replaces comprises 4-chlorobutyroyl chloride, 4-bromo butyryl bromide etc.The butyryl halogen that preferred 4-halogen replaces is the 4-chlorobutyroyl chloride.Be reflected in the solvent and carry out, as dithiocarbonic anhydride, 1,2-ethylene dichloride, normal hexane, acetonitrile, 1-nitropropane, Nitromethane 99Min., ether, tetracol phenixin, methylene dichloride, tetrachloroethane or oil of mirbane, wherein methylene dichloride is preferred solvent.Reaction can be carried out in 0 ℃ to 40 ℃ temperature range 1/2 to 25 hours.Preferred churning time is 6 hours.Preferred temperature is 40 ℃.The mixture of ω-halo-α-ketone group-phenylacetamide (3) that a contraposition and a position replace reclaims from responding layer through extracting method known in the art by the water quenching again.

The used suitable Lewis acid of the acylation reaction of describing in step B is this area understanding and knows.Suitable lewis acidic example is boron trichloride, aluminum chloride, titanium tetrachloride, boron trifluoride, tin tetrachloride and zinc chloride.The suitable lewis acidic selection and the use that are used for step B acylation reaction are that those of ordinary skills are familiar with and know.

ω-the halo of para-orientation-α-ketone group-phenylacetamide (3) is able to purifying by the described recrystallization technology of step C.

For example, the product of the extracting method described in the step B is at suitable organic solvent, as being stirred and collect in heptane/ethyl acetate (about 4: 1) mixture.Solid is dissolved in appropriate solvent such as ethyl acetate in 25 ℃ to 76 ℃ temperature range.Preferred temperature is 76 ℃.Then solution is contacted with gac.Dilute with the mixture filtration and with appropriate solvent such as heptane.The soup compound of gained is heated to the acquisition uniform solution.Room temperature leaves standstill, the ω-halo of pure basically para-orientation-α-ketone group-phenylacetamide (4) crystallization and going out.

In step D, the ω-halo of pure basically para-orientation-α-ketone group-phenylacetamide (4) is hydrolyzed, and generates 4-(cyclopropyl carbonyl) toluylic acid (5).

For example, the ω-halo of pure basically para-orientation-α-ketone group-phenylacetamide (4) contacts in appropriate solvent such as ethanol with the suitable alkali such as the potassium hydroxide of molar excess.Reactant stirred in 0 ℃ to 78 ℃ temperature range 1 to 24 hour usually together.Preferred churning time is 18 hours.Preferred temperature is 25 ℃.4-(cyclopropyl carbonyl) toluylic acid (5) reclaims from responding layer by acidifying and extracting method known in the art.

In step e, 4-(cyclopropyl carbonyl) toluylic acid (5) is esterified, generates corresponding 4-(cyclopropyl carbonyl) phenylacetate (6).

For example, in 25 ℃ to 78 ℃ temperature range, 4-(cyclopropyl carbonyl) toluylic acid (5) and excessive suitable straight or branched C ₁～C ₆Alcohol reacts in the presence of the mineral acid example hydrochloric acid of catalytic amount or vitriolic, wherein hydrochloric acid preferably.Reactant was stirred 2 to 72 hours usually together.Preferred churning time is 24 hours.Preferred temperature is 25 ℃.Corresponding 4-(cyclopropyl carbonyl) phenylacetate (6) reclaims from responding layer by alkalization and extracting method known in the art.It can be able to purifying by silica gel chromatography.

In step F, 4-(cyclopropyl carbonyl) phenylacetate (6) generates corresponding [4-(cyclopropyl carbonyl) phenyl] diester malonate (7) with suitable acylating reagent acidylate.

For example, 4-(cyclopropyl carbonyl) phenylacetate (6) and the suitable acylating reagent reaction of molar excess slightly.Suitable acylating reagent comprises dialkyl carbonate such as dimethyl carbonate or diethyl carbonate, or chloro-formic ester such as methyl-chloroformate or Vinyl chloroformate.Be reflected at 0 ℃ to the solvent refluxing temperature, in the presence of non-nucleophilicity alkali, in suitable aprotic solvent, carried out 0.5 hour to 7 days.Preferred churning time is 3 days.Preferred temperature is 25 ℃.The appropriate solvent of acylation reaction comprises tetrahydrofuran (THF), dioxane, or t-butyl methyl ether.Preferred solvent is a tetrahydrofuran (THF).The suitable non-nucleophilicity alkali of acylation reaction comprises mineral alkali such as sodium bicarbonate, saleratus, or hydride such as sodium hydride or potassium hydride KH, or alkoxide, as potassium tert.-butoxide.Preferred alkali is two (trimethyl silyl) ammonification sodium (sodiumbis (trimethylsilyl) amide).

After the acidylate, the derivative that acidylate forms randomly carries out the original position alkylation with suitable alkylating reagent.Suitable alkylating reagent comprises haloalkane such as methyl iodide, methyl chloride or monobromethane, or dialkylsulfates, as dimethyl sulphide acid esters or diethyl sulfide acid esters.Reactant stirred in 0 ℃ to 30 ℃ temperature range 1 to 48 hour usually together.Preferred churning time is 24 hours.Preferred temperature is 25 ℃.

[4-(cyclopropyl carbonyl) phenyl] diester malonate (7) reclaims from responding layer by extracting method known in the art accordingly.It can be able to purifying by silica gel chromatography and/or recrystallization.

Although in acidylate in step F and the ensuing alkylation is not essential, the ketone group functional group of 4-(cyclopropyl carbonyl) phenylacetate (6) can protect with suitable protecting group.It is well known to those of ordinary skill in the art being used for protecting the selection and the use of suitable protecting group of the ketone group of structural formula (6); at " Protective Groups in Organicsynthesis "; Theodora W.Greene describes among the Wiley (1981) to some extent.For example, the suitable blocking group of protection ketone group functional group comprises aliphatics ketal such as dimethyl ketal, and cyclic ketal is as 1; 3-dioxane and 1; 3-dioxalane, aliphatics dithio ketal such as S, S-dimethyl ketal; ring-type dithio ketal is as 1; 3-dithiane and 1,3-dithiolane derivative, aliphatic single sulfo-ketal; the single sulfo-ketal of ring-type is as 1,3-oxathiolanes.

In step G, [4-(cyclopropyl carbonyl) phenyl] diester malonate (7) is generated corresponding [4-(4-halo-1-oxo-butyl) phenyl] diester malonate (8) by open loop.

For example, [4-(cyclopropyl carbonyl) phenyl] diester malonate (7) contacts in suitable organic solvent or when solvent-free with suitable hydrogen halide such as hydrogenchloride, hydrogen bromide or hydrogen iodide.In 0 ℃～100 ℃ temperature range, suitable organic solvent comprises alcoholic solvent such as ethanol, methyl alcohol, Virahol or propyl carbinol, varsol such as benzene, toluene or dimethylbenzene, halohydrocarbon such as chlorobenzene, chloroform or methylene dichloride, or dimethyl formamide, or acetate, or dioxane.Preferably solvent-free.Reactant stirred 1 to 24 hour usually together.Preferred churning time is 4 to 16 hours.Preferred temperature range is 60 ℃ to 80 ℃.If there is solvent, [4-(4-halo-1-oxo-butyl) phenyl] diester malonate (8) reclaims and then boils off solvent by extracting method known in the art from responding layer.

In step H, the halogen functional group of [4-(4-halo-1-oxo-butyl) phenyl] diester malonate (8) generates corresponding [4-[4-[4-(hydroxyl diphenyl-methyl)-piperidino]-1-oxygen-butyl with α-(4-pyridyl) diphenyl-carbinol (can buy from Aldrich Chemicals) alkylation] phenyl] diester malonate (9).

For example, alkylated reaction in appropriate solvent, preferably in the presence of non-nucleophilicity alkali, optional is carries out in the presence of the iodide source of catalytic amount such as potassiumiodide or sodium iodide.Reaction times is about 4 hours to 7 days, temperature of reaction be 25 ℃ to the solvent refluxing temperature.Preferred churning time is 3 days.Preferred temperature is the solvent refluxing temperature.The appropriate solvent of alkylated reaction comprises alcoholic solvent such as methyl alcohol, ethanol, Virahol or propyl carbinol, ketones solvent such as methyl iso-butyl ketone (MIBK), the mixture of varsol such as benzene, toluene or dimethylbenzene and they and water, halogenated hydrocarbon such as chlorobenzene or methylene dichloride, or dimethyl formamide.Preferred solvent is toluene (10: 4).The suitable non-nucleophilicity alkali of alkylated reaction comprises mineral alkali such as sodium bicarbonate, saleratus or salt of wormwood, or organic bases such as trialkylamine such as triethylamine or pyridine, perhaps can use excessive α-(4-pyridyl) diphenyl-carbinol.Preferred alkali is salt of wormwood.

[4-[4-[4-(hydroxyl diphenyl-methyl)-piperidino]-1-oxygen-butyl accordingly] phenylmalonic acid diester (9) reclaims from responding layer by extracting method known in the art.It can be able to purifying by silica gel chromatography.

Although in the alkylation of step H, be not essential, can the ketone group functional group in [4-(4-halo-1-oxo-butyl) phenyl] diester malonate (8) be protected with suitable protecting group.It is well known to those of ordinary skill in the art being used for protecting the selection and the use of the suitable protecting group of structural formula (8) ketone group; it is at " Protective Groups in Organicsynthesis "; Theodora W.Greene describes among the Wiley (1981) to some extent.For example, the suitable protecting group of ketone group functional group comprises aliphatics ketal such as dimethyl ketal, and cyclic ketal is as 1; 3-dioxane and 1; 3-dioxalanes, aliphatics dithio ketal such as S, S-dimethyl ketal; ring-type dithio ketal is as 1; 3-dithiane and 1,3-dithiolane derivative, the single sulfo-ketal of aliphatics; the single sulfo-ketal of ring-type is as 1,3-oxathiolanes.

In the step I, [4-[4-[4-(hydroxyl diphenyl-methyl)-piperidino]-1-oxygen-butyl] phenyl] diester malonate (9) optionally is reduced into corresponding 4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-phenylacetate (10).This finishes by utilizing a suitable selectivity reductibility reagent.Suitable selectivity reductibility reagent is the combination of a kind of reagent or plurality of reagents, it can be optionally only be reduced into corresponding hydroxymethyl part with an ester group in the diester malonate functional group, does not reduce second ester group in the diester malonate functional group simultaneously.Suitable selectivity reduction reagent comprises three tert.-butoxy lithium aluminium hydride, or the share of suitable silane and suitable (titanocene-based) catalyzer based on two luxuriant titaniums.

For example, [4-[4-[4-(hydroxyl diphenyl-methyl)-piperidino]-1-oxygen-butyl] phenyl] diester malonate (9) and suitable selectivity also original reagent contact in appropriate solvent such as tetrahydrofuran (THF), ether or dioxane as three tert.-butoxy lithium aluminium hydride.Preferred solvent is a tetrahydrofuran (THF).Reactant stirred in 0 ℃ to 65 ℃ temperature range 0.5 to 168 hour usually together.Preferred churning time is 48 hours.Preferred temperature is 25 ℃.

By [4-[4-[4-(hydroxyl diphenyl-methyl)-piperidino]-1-oxygen-butyl] phenyl] diester malonate (9) preparation 4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-phenylacetate (10), also can adopt catalytic reduction, use for example suitable catalyzer based on two luxuriant titaniums, wherein suitable silane is as the reductive agent of poly-hydrogenated methyl silane as stoichiometric quantity.The suitable catalyzer based on two luxuriant titaniums comprises the so-called " Cp of activatory ₂TiH " the catalysis kind.By, for example in appropriate solvent such as tetrahydrofuran (THF) to 1 normal Cp ₂TiCl ₂The middle 2 normal ethylmagnesium bromide that add are with synthetic activatory catalysis kind " Cp ₂TiH ", be well known to those of ordinary skill in the art.

For example, catalytic reduction carries out to the temperature range of solvent refluxing temperature at about 25 ℃ in appropriate solvent such as tetrahydrofuran (THF) or ether or dioxane.The preferred temperature that catalytic reduction uses is 65 ℃.Reaction times is 8 to 24 hours.Preferred churning time is 18 hours.4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-phenylacetate (10) can by with Bu ₄Reclaim from responding layer with extracting method known in the art NF effect back.It can be able to purifying by silica gel chromatography.

In addition, with [4-[4-[4-(hydroxyl diphenyl-methyl)-piperidino]-1-oxygen-butyl] phenyl] pure 4-[1-hydroxyl-4-[4-(hydroxyl the diphenyl-methyl)-piperidino of diester malonate (9) preparation optics (enantiomerically)] butyl]-α-(methylol)-phenylacetate (10), can adopt the chiral catalysis reduction, use suitable chirality two luxuriant titanium systems, as Journal of American ChemicalSociety, described in 116,11667～11670 (1994).

Those skilled in the art will appreciate that protected [4-[4-[4-(hydroxyl diphenyl-methyl)-the piperidino]-1-oxygen-butyl of ketone group] phenylmalonic acid diester (9) before the reduction reaction that the step I is described must with suitable deprotecting regent reaction.The selection of suitable deprotecting regent and use are well known to those of ordinary skill in the art, and at " Protective Groups in Organicsynthesis ", Theodora W.Greene describes among the Wiley (1981) to some extent.For example, [4-[4-[4-(hydroxyl diphenyl-methyl)-piperidino]-1-oxygen-butyl] phenyl] the cracking of dimethyl ketal protecting group in diester malonate (9) the ketone group functional group can finish by using iodine trimethyl silane or diluted acid known in the art.

In step J, randomly to 4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-phenylacetate (10) is hydrolyzed, and generates corresponding 4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-toluylic acid (11).

For example, hydrolysis can be finished by methods known in the art, as the salt of wormwood in methyl alcohol, methanol ammonium hydroxide, salt of wormwood, potassium hydroxide, calcium hydroxide, sodium hydroxide, magnesium hydroxide, sodium hydroxide/pyridine, potassium cyanide in ethanol and the sodium hydroxide in aqueous alcohol in methyl alcohol, sodium hydroxide preferably wherein.Reaction is carried out in aqueous lower alcohol solvent such as methyl alcohol, ethanol, Virahol, propyl carbinol, cellosolvo or ethylene glycol or pyridine usually.Preferred solvent is tetrahydrofuran (THF)/methanol (3: 2: 1) mixture.Reaction is carried out to the temperature range of solvent refluxing temperature in room temperature usually.Preferred temperature is 65 ℃.Reactant stirred 1 to 24 hour usually together.Preferred churning time is 4 hours.4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-toluylic acid (11) reclaims from responding layer by acidifying and extracting method known in the art.

Certainly, molecular formula may exist with multiple steric isomer as the compound of (I).This compound has the chiral centre more than.For example, the benzyl carbon that is connected of carboxyl, methylol and methyl may with (R) or (S) form exist.In addition, the benzyl carbon of hydroxyl, the connection of hydrogen atom alkylamino may be with (R) or (S) form existence.Can further understand thus, the present invention comprises various structures and the stereoisomerism configuration of molecular formula as the compound of (I),, comprises independent isomer and mixture of isomers that is.

Schema B has listed the another kind of new preparation method of 4-(cyclopropyl carbonyl) toluylic acid.This compound is used for compound and fexofenadine and the related compound of synthetic molecules formula as (I).In schema B, R ₁Be C ₁～C ₆Alkyl, its C ₁～C ₆Moieties is a straight or branched.

Schema B

In the step a of schema B, phenylacetate (1), its R ₁Be C ₁～C ₆Alkyl, its C ₁～C ₆Moieties is a straight or branched, by the butyryl halogen acidylate that the following 4-halogen of suitable molecular formula replaces, generates the ω-halo-α-ketone group-phenylacetate (2) of corresponding contraposition, a position replacement under the Friedel-Crafts condition, and wherein X is Cl, Br or I,

Wherein, each X independently represents Cl, Br or I.

For example, in step a, phenylacetate (1) contacts with suitable Lewis acid under the general condition of Friedel-Crafts acidylate with the butyryl halogen that the 4-halogen replaces.The example of the butyryl halogen that suitable 4-halogen replaces comprises 4-chlorobutanoylchloride, 4-bromine butyryl bromide etc.The butyryl halogen that preferred 4-halogen replaces is the 4-chlorobutanoylchloride.Be reflected in the solvent and carry out, as dithiocarbonic anhydride, 1,2-ethylene dichloride, normal hexane, acetonitrile, 1-nitropropane, Nitromethane 99Min., ether, tetracol phenixin, methylene dichloride, tetrachloroethane or oil of mirbane, wherein preferred solvent is a methylene dichloride.The anticaustic time, temperature of reaction was between 0 ℃ to 40 ℃ between about 1/2 to 25 hour.ω-halo-α-ketone group-phenylacetate (2) that contraposition, a position replace reclaims from responding layer through extracting method known in the art by the water quenching again.

The suitable Lewis acid of describing among the step a that is used for acylation reaction is this area understanding and knows.Suitable lewis acidic example is boron trichloride, aluminum chloride, titanium tetrachloride, boron trifluoride, tin tetrachloride and zinc chloride.The suitable lewis acidic selection and the use that are used for acidylate among the step a are that those of ordinary skills are familiar with and know.

In the step b of schema B, the ω-halo of a position and para-orientation-α-ketone group-phenylacetate (2) mixture is hydrolyzed, (cyclopropyl carbonyl) toluylic acid (3) mixture of position and para-orientation between generation.

For example, the suitable alkali of ω-halo-α-ketone group-phenylacetate (2) mixture of a position and para-orientation and molar excess such as lithium hydroxide or potassium hydroxide contact in appropriate solvent such as ethanol.Reactant stirred in 0 ℃ to 78 ℃ temperature range 1 to 24 hour usually together.Preferred churning time is 18 hours.Preferred temperature is 25 ℃.Between position and (cyclopropyl carbonyl) toluylic acid (3) of para-orientation can from responding layer, reclaim by acidifying and extracting method known in the art.

Surprisingly, pure basically para-isomeride can separate at an easy rate by listed crystallization among the schema B step c thereafter.

For example, the product reflux with the extracting method listed among the step b is dissolved in the suitable organic solvent as heptane/ethyl acetate (about 4: 1) mixture.Solution also filters with activated carbon treatment.After the cooling, the solid that collect to generate and through suitable organic solvent such as ethyl acetate/heptane recrystallization.Basically (cyclopropyl carbonyl) toluylic acid (4) of pure para-orientation goes out through the static crystallization of room temperature.

As indicated earlier, 4-(cyclopropyl carbonyl) toluylic acid in the compound of synthetic molecules formula I as intermediate.Shown in schema C, 4-(cyclopropyl carbonyl) toluylic acid also can be used as intermediate in the method for preparation molecular formula as the compound of (7).Molecule comprises fexofenadine and relevant compound suc as formula the compound of (7).

Schema C

In the step a of schema C, 4-(cyclopropyl carbonyl) toluylic acid (1) is esterified under the condition that schema A step e is listed, and generates corresponding 4-(cyclopropyl carbonyl) phenylacetate (2), wherein R ₁Be C ₁～C ₆Alkyl, its C ₁～C ₆Moieties is a straight or branched.

In schema C step b, 4-(cyclopropyl carbonyl) phenylacetate (2) generates alkylating accordingly [4-(cyclopropyl carbonyl) phenyl] phenylacetate (3), wherein R with suitable alkylated ₁With define among the preceding step a identical, R ₂And R ₃Independently represent C ₁～C ₆Alkyl, its C ₁～C ₆Moieties is a straight or branched.

For example, reaction in the presence of suitable non-nucleophilicity alkali, is carried out in suitable aprotic solvent usually.The appropriate solvent of alkylated reaction comprises diglyme, tetrahydrofuran (THF), dioxane t-butyl methyl ether.Preferred solvent is a diglyme.The suitable non-nucleophilicity alkali that is used for alkylated reaction comprises two (trimethyl silyl) ammonification sodium, mineral alkali such as sodium bicarbonate, saleratus, or hydride such as sodium hydride or potassium hydride KH, or alkoxide such as potassium tert.-butoxide.Preferred alkali is potassium tert.-butoxide.Suitable alkylating reagent comprises halohydrocarbon such as methyl iodide, methyl chloride or monobromethane, or dialkylsulfates such as dimethyl sulphide acid esters or diethyl sulfide acid esters.Reactant stirred 1 to 48 hour together 0 ℃ to 80 ℃ temperature range usually.

Among the step c of schema C, alkylating [4-(cyclopropyl carbonyl) phenyl] phenylacetate (3) is generated corresponding [4-(4-halo-1-oxo-butyl) phenyl] phenylacetate (4), wherein R by open loop ₁, R ₂And R ₃With define among the preceding step b identical, X is Cl, Br or I.Be reflected under the condition of listing among the step G of schema A and carry out.

In steps d, [4-(4-halo-1-oxo-butyl) phenyl] phenylacetate (4) is at U.S.P.No.4,254, in 129 under the disclosed condition, by α-(4-pyridyl) diphenyl-carbinol alkylation, generate [4-[4-[4-(hydroxyl diphenyl-methyl)-piperidino]-1-oxygen-butyl] phenyl] phenylacetate (5), wherein R ₁, R ₂And R ₃With define among the preceding step b identical, the document is incorporated herein for referencial use.

In the step e of schema C, [4-[4-[4-(hydroxyl diphenyl-methyl)-piperidino]-1-oxygen-butyl] phenyl] phenylacetate (5) is at U.S.P.No.4,254, in 129 under the disclosed condition with suitable reduction reagent react, generate 4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl] phenylacetate (6), wherein R ₁, R ₂And R ₃With define among the preceding step b identical.Suitable reduction reagent comprises, for example, and sodium borohydride or POTASSIUM BOROHYDRIDE.Use the catalytic reduction of Raney nickel, palladium, platinum or rhodium catalyst also can be used among the step e of schema C.

In the step f of schema C, to 4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl] phenylacetate (6) is at U.S.P.No.4,254, disclosed condition randomly is hydrolyzed in 129, generate 4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl] toluylic acid (7), wherein R ₂And R ₃With define among the preceding step b identical.

Although be not essential in alkylation step b and d, the ketone group functional group of 4-(cyclopropyl carbonyl) phenylacetate (6) can protect with suitable protecting group.It is well known to those of ordinary skill in the art being used for protecting the selection and the use of suitable protecting group of the ketone group of structural formula (6); at " Protective Groupsin Organic synthesis "; Theodora W.Greene describes among the Wiley (1981) to some extent.For example, the suitable blocking group of protection ketone group functional group comprises aliphatics ketal such as dimethyl ketal, and cyclic ketal is as 1; 3-dioxane and 1; 3-dioxalane, aliphatics dithio ketal such as S, S-dimethyl ketal; ring-type dithio ketal is as 1; 3-dithiane and 1,3-dithiolane derivative, aliphatic single sulfo-ketal; the single sulfo-ketal of ring-type is as 1,3-oxathiolanes.

Provided the representational embodiment of synthetic that describes among schema A, B and the C below.The starting raw material that is used for schema A, B and C is easy to obtain for those of ordinary skills.These embodiment only are illustrative and do not attempt that in office where face limits the scope of the invention.It is as follows that following term is used for this paper (running through whole specification sheets) meaning: " g " refers to gram; " mmol " refers to mmole; " mL " refers to milliliter; " bp " refers to boiling point; " mp " refers to fusing point; " ℃ " refer to degree centigrade; " mm Hg " refers to mmhg; " μ L " refers to microlitre; " μ g " refers to microgram; " μ M " refers to the micromole.

The synthetic embodiment that lists among the schema A

Steps A: the preparation of N-methoxyl group-N-methyl-phenylacetamide

(100g 720mmol) is dissolved in the water (100ml) with salt of wormwood.Add phenyllacetyl chloride (50g, toluene 320mmol) (250ml) solution.Then in 1 hour, dropwise add N-O-dimethyl oxammonium hydrochloride (32g, water 330mmol) (100mL) solution.After three hours, careful adding 10% hydrochloric acid (250mL) and t-butyl methyl ether (125mL).Separate organic phase, with 10% hydrochloric acid and saturated sodium bicarbonate solution washing.Dry and the concentrated title compound (55g, 95%) that provides on anhydrous magnesium sulfate.

Step B:[4-(4-chloro-1-oxygen-butyl)]-preparation of N-methoxyl group-N-methylbenzene ethanamide

Cool off aluminum chloride (87g, methylene dichloride 650mmol) (100mL) pulpous state liquid with ice bath.In 0.5 hour, dropwise add the 4-chlorobutanoylchloride (51g, 360mL).In 0.5 hour, add again N-methoxyl group-N-methylbenzene ethanamide (53g, 300mmol).Question response solution is warmed to room temperature.Then reflux is 6 hours.After treating that solution is cooled to room temperature, be poured in the ice (1L) and add methylene dichloride (1L).Separate organic phase.With methylene dichloride (2 * 500mL) aqueous phase extracted.The organic phase that merges with anhydrous magnesium sulfate drying, and concentrate the solid that contains about 1: 1 mixture of title compound and its meta-isomer with generation.

Step C:[4-(4-chloro-1-oxygen-butyl)]-crystallization of N-methoxyl group-N-methyl-phenylacetamide

The solid that obtains among the step B is placed heptane/ethyl acetate (about 4: 1) pulp liquid, then collect it.Solid is dissolved in the solution of also using about 5g activated carbon treatment gained in the hot ethyl acetate.Filter and adding heptane (60mL) with diatomite.Heating pulpous state liquid is until obtaining uniform solution.The placement of solution room temperature is spent the night.Filter the crystalline solid that generates and use heptane wash, obtain [4-(4-chloro-1-oxygen-butyl)]-N-methoxyl group-N-methyl-phenylacetamide (20g) of purifying.Mother liquor was placed 5 days and collected second section crystalline solid (3.0g), obtain [4-(4-chloro-1-oxygen-butyl)]-N-methoxyl group-N-methyl-phenylacetamide of 23g (28%) purifying altogether.

The preparation of step D:4-(cyclopropyl carbonyl) toluylic acid

(9.4g 330mmol) is added in ethanol (160mL) solution of potassium hydroxide (22.0g) with [4-(4-chloro-1-oxygen-butyl)]-N-methoxyl group-N-methyl-phenylacetamide of purifying.Stirred 18 hours.In solution impouring dilute hydrochloric acid (the 30mL concentrated hydrochloric acid is dissolved in the 500mL water).With three parts of 500mL ethyl acetate extraction solution.Organic phase and the concentrated title compound (6.4g, 95%) that obtains with the anhydrous magnesium sulfate drying merging.

The preparation of step e: 4-(cyclopropyl carbonyl) Phenylacetic acid ethylester

4-(cyclopropyl carbonyl) toluylic acid is dissolved in the ethanol (150mL) that contains the vitriol oil (10).Stirred 24 hours.Add triethylamine (2mL) and concentrated solution.Residuum is dissolved in water/ethyl acetate.Wash organic phase with saturated sodium bicarbonate solution, anhydrous magnesium sulfate drying also concentrates.With silica gel chromatography (400mL silica gel, 20% ethyl acetate/heptane is as eluent) purifying, obtain title compound (7.0g, 88%).

The preparation of step e: 4-(cyclopropyl carbonyl) methyl phenylacetate

4-(cyclopropyl carbonyl) toluylic acid is dissolved in the methyl alcohol (100mL) that contains the vitriol oil (10).Stirred 24 hours.Add triethylamine (2mL) and concentrated solution.Residuum is dissolved in water/ethyl acetate.Wash organic phase with saturated sodium bicarbonate solution, anhydrous magnesium sulfate drying also concentrates.With silica gel chromatography (400mL silica gel, 20% ethyl acetate/heptane is as eluent) purifying, obtain title compound (4.6g, 68%).

Step F: the preparation of [4-(cyclopropyl carbonyl) phenyl] methyl-diethyl malonate

With 4-(cyclopropyl carbonyl) Phenylacetic acid ethylester (6.5g, 28mmol) and diethyl carbonate (4.0g 34mmol) is dissolved in the tetrahydrofuran (THF) (100mL).The tetrahydrofuran solution that in 0.5 hour, adds 1.0 moles of two (trimethyl silyl) ammonification sodium of 62mL (62mmol).Stirred 28 hours.The adding methyl iodide (5.3g, 35mmol).Stirred 2 days.Add entry and ethyl acetate.With salt water washing organic phase, with anhydrous magnesium sulfate drying and concentrated.By flash chromatography (200g silica gel, ethyl acetate/heptane is as eluent) purifying, obtain title compound (1.43g, 17%).

Step F: the preparation of [4-(cyclopropyl carbonyl) phenyl] methyl-dimethyl malonate

With 4-(cyclopropyl carbonyl) methyl phenylacetate (1.5g, 6.0mmol) and dimethyl carbonate (930mg 10.3mmol) is dissolved in tetrahydrofuran (THF) (10mL).The tetrahydrofuran solution that in 0.5 hour, adds 1.0 moles of two (trimethyl silyl) ammonification sodium of 20mL (20mmol).Stirred 3 days.The adding methyl iodide (5.3g, 35mmol).Stirred 24 hours.Add entry and ethyl acetate.With salt water washing organic phase, with anhydrous magnesium sulfate drying and concentrated.By flash chromatography (50g silica gel, ethyl acetate/heptane is as eluent) purifying, obtain title compound (315mg, 16%).

In addition, following compounds can prepare by the building-up process that step F is described:

[4-(cyclopropyl carbonyl) phenyl] methyl-propanedioic acid, the ethyl-methyl diester

[4-(cyclopropyl carbonyl) phenyl] methyl-propanedioic acid, the methyl-propyl diester

[4-(cyclopropyl carbonyl) phenyl] methyl-propanedioic acid, the butyl methyl diester

[4-(cyclopropyl carbonyl) phenyl] methyl-propanedioic acid, the methyl amyl diester

[4-(cyclopropyl carbonyl) phenyl] methyl-propanedioic acid, the hexyl methyl diester

[4-(cyclopropyl carbonyl) phenyl] methyl-propanedioic acid, the ethyl propyl diester

[4-(cyclopropyl carbonyl) phenyl] methyl-propanedioic acid, the butyl ethyl diester

[4-(cyclopropyl carbonyl) phenyl] methyl-propanedioic acid, the ethyl pentyl group diester

[4-(cyclopropyl carbonyl) phenyl] methyl-propanedioic acid, the ethylhexyl diester

[4-(cyclopropyl carbonyl) phenyl] methyl-propanedioic acid, dipropyl

[4-(cyclopropyl carbonyl) phenyl] methyl-propanedioic acid, butyl propyl group diester

[4-(cyclopropyl carbonyl) phenyl] methyl-propanedioic acid, amyl group propyl group diester

[4-(cyclopropyl carbonyl) phenyl] methyl-propanedioic acid, hexyl propyl group diester

[4-(cyclopropyl carbonyl) phenyl] methyl-propanedioic acid, dibutylester

[4-(cyclopropyl carbonyl) phenyl] methyl-propanedioic acid, butyl amyl group diester

[4-(cyclopropyl carbonyl) phenyl] methyl-propanedioic acid, butyl hexyl diester

[4-(cyclopropyl carbonyl) phenyl] methyl-propanedioic acid, diamyl ester

[4-(cyclopropyl carbonyl) phenyl] methyl-propanedioic acid, hexyl amyl group diester

[4-(cyclopropyl carbonyl) phenyl] methyl-propanedioic acid, dihexyl

[4-(cyclopropyl carbonyl) phenyl] ethyl-propanedioic acid, diethyl ester

[4-(cyclopropyl carbonyl) phenyl] ethyl-propanedioic acid, dimethyl ester

[4-(cyclopropyl carbonyl) phenyl] ethyl-propanedioic acid, the ethyl-methyl diester

[4-(cyclopropyl carbonyl) phenyl] ethyl-propanedioic acid, the methyl-propyl diester

[4-(cyclopropyl carbonyl) phenyl] ethyl-propanedioic acid, the butyl methyl diester

[4-(cyclopropyl carbonyl) phenyl] ethyl-propanedioic acid, the methyl amyl diester

[4-(cyclopropyl carbonyl) phenyl] ethyl-propanedioic acid, the hexyl methyl diester

[4-(cyclopropyl carbonyl) phenyl] ethyl-propanedioic acid, the ethyl propyl diester

[4-(cyclopropyl carbonyl) phenyl] ethyl-propanedioic acid, the butyl ethyl diester

[4-(cyclopropyl carbonyl) phenyl] ethyl-propanedioic acid, the ethyl pentyl group diester

[4-(cyclopropyl carbonyl) phenyl] ethyl-propanedioic acid, the ethylhexyl diester

[4-(cyclopropyl carbonyl) phenyl] ethyl-propanedioic acid, dipropyl

[4-(cyclopropyl carbonyl) phenyl] ethyl-propanedioic acid, butyl propyl group diester

[4-(cyclopropyl carbonyl) phenyl] ethyl-propanedioic acid, amyl group propyl group diester

[4-(cyclopropyl carbonyl) phenyl] ethyl-propanedioic acid, hexyl propyl group diester

[4-(cyclopropyl carbonyl) phenyl] ethyl-propanedioic acid, dibutylester

[4-(cyclopropyl carbonyl) phenyl] ethyl-propanedioic acid, butyl amyl group diester

[4-(cyclopropyl carbonyl) phenyl] ethyl-propanedioic acid, butyl hexyl diester

[4-(cyclopropyl carbonyl) phenyl] ethyl-propanedioic acid, diamyl ester

[4-(cyclopropyl carbonyl) phenyl] ethyl-propanedioic acid, hexyl amyl group diester

[4-(cyclopropyl carbonyl) phenyl] ethyl-propanedioic acid, dihexyl

[4-(cyclopropyl carbonyl) phenyl] propyl group-propanedioic acid, diethyl ester

[4-(cyclopropyl carbonyl) phenyl] propyl group-propanedioic acid, dimethyl ester

[4-(cyclopropyl carbonyl) phenyl] propyl group-propanedioic acid, the ethyl-methyl diester

[4-(cyclopropyl carbonyl) phenyl] propyl group-propanedioic acid, the methyl-propyl diester

[4-(cyclopropyl carbonyl) phenyl] propyl group-propanedioic acid, the butyl methyl diester

[4-(cyclopropyl carbonyl) phenyl] propyl group-propanedioic acid, the methyl amyl diester

[4-(cyclopropyl carbonyl) phenyl] propyl group-propanedioic acid, the hexyl methyl diester

[4-(cyclopropyl carbonyl) phenyl] propyl group-propanedioic acid, the ethyl propyl diester

[4-(cyclopropyl carbonyl) phenyl] propyl group-propanedioic acid, the butyl ethyl diester

[4-(cyclopropyl carbonyl) phenyl] propyl group-propanedioic acid, the ethyl pentyl group diester

[4-(cyclopropyl carbonyl) phenyl] propyl group-propanedioic acid, the ethylhexyl diester

[4-(cyclopropyl carbonyl) phenyl] propyl group-propanedioic acid, dipropyl

[4-(cyclopropyl carbonyl) phenyl] propyl group-propanedioic acid, butyl propyl group diester

[4-(cyclopropyl carbonyl) phenyl] propyl group-propanedioic acid, amyl group propyl group diester

[4-(cyclopropyl carbonyl) phenyl] propyl group-propanedioic acid, hexyl propyl group diester

[4-(cyclopropyl carbonyl) phenyl] propyl group-propanedioic acid, dibutylester

[4-(cyclopropyl carbonyl) phenyl] propyl group-propanedioic acid, butyl amyl group diester

[4-(cyclopropyl carbonyl) phenyl] propyl group-propanedioic acid, butyl hexyl diester

[4-(cyclopropyl carbonyl) phenyl] propyl group-propanedioic acid, diamyl ester

[4-(cyclopropyl carbonyl) phenyl] propyl group-propanedioic acid, hexyl amyl group diester

[4-(cyclopropyl carbonyl) phenyl] propyl group-propanedioic acid, dihexyl

[4-(cyclopropyl carbonyl) phenyl] butyl-propanedioic acid, diethyl ester

[4-(cyclopropyl carbonyl) phenyl] butyl-propanedioic acid, dimethyl ester

[4-(cyclopropyl carbonyl) phenyl] butyl-propanedioic acid, the ethyl-methyl diester

[4-(cyclopropyl carbonyl) phenyl] butyl-propanedioic acid, the methyl-propyl diester

[4-(cyclopropyl carbonyl) phenyl] butyl-propanedioic acid, the butyl methyl diester

[4-(cyclopropyl carbonyl) phenyl] butyl-propanedioic acid, the methyl amyl diester

[4-(cyclopropyl carbonyl) phenyl] butyl-propanedioic acid, the hexyl methyl diester

[4-(cyclopropyl carbonyl) phenyl] butyl-propanedioic acid, the ethyl propyl diester

[4-(cyclopropyl carbonyl) phenyl] butyl-propanedioic acid, the butyl ethyl diester

[4-(cyclopropyl carbonyl) phenyl] butyl-propanedioic acid, the ethyl pentyl group diester

[4-(cyclopropyl carbonyl) phenyl] butyl-propanedioic acid, the ethylhexyl diester

[4-(cyclopropyl carbonyl) phenyl] butyl-propanedioic acid, dipropyl

[4-(cyclopropyl carbonyl) phenyl] butyl-propanedioic acid, butyl propyl group diester

[4-(cyclopropyl carbonyl) phenyl] butyl-propanedioic acid, amyl group propyl group diester

[4-(cyclopropyl carbonyl) phenyl] butyl-propanedioic acid, hexyl propyl group diester

[4-(cyclopropyl carbonyl) phenyl] butyl-propanedioic acid, dibutylester

[4-(cyclopropyl carbonyl) phenyl] butyl-propanedioic acid, butyl amyl group diester

[4-(cyclopropyl carbonyl) phenyl] butyl-propanedioic acid, butyl hexyl diester

[4-(cyclopropyl carbonyl) phenyl] butyl-propanedioic acid, diamyl ester

[4-(cyclopropyl carbonyl) phenyl] butyl-propanedioic acid, hexyl amyl group diester

[4-(cyclopropyl carbonyl) phenyl] butyl-propanedioic acid, dihexyl

[4-(cyclopropyl carbonyl) phenyl] amyl group-propanedioic acid, diethyl ester

[4-(cyclopropyl carbonyl) phenyl] amyl group-propanedioic acid, dimethyl ester

[4-(cyclopropyl carbonyl) phenyl] amyl group-propanedioic acid, the ethyl-methyl diester

[4-(cyclopropyl carbonyl) phenyl] amyl group-propanedioic acid, the methyl-propyl diester

[4-(cyclopropyl carbonyl) phenyl] amyl group-propanedioic acid, the butyl methyl diester

[4-(cyclopropyl carbonyl) phenyl] amyl group-propanedioic acid, the methyl amyl diester

[4-(cyclopropyl carbonyl) phenyl] amyl group-propanedioic acid, the hexyl methyl diester

[4-(cyclopropyl carbonyl) phenyl] amyl group-propanedioic acid, the ethyl propyl diester

[4-(cyclopropyl carbonyl) phenyl] amyl group-propanedioic acid, the butyl ethyl diester

[4-(cyclopropyl carbonyl) phenyl] amyl group-propanedioic acid, the ethyl pentyl group diester

[4-(cyclopropyl carbonyl) phenyl] amyl group-propanedioic acid, the ethylhexyl diester

[4-(cyclopropyl carbonyl) phenyl] amyl group-propanedioic acid, dipropyl

[4-(cyclopropyl carbonyl) phenyl] amyl group-propanedioic acid, butyl propyl group diester

[4-(cyclopropyl carbonyl) phenyl] amyl group-propanedioic acid, amyl group propyl group diester

[4-(cyclopropyl carbonyl) phenyl] amyl group-propanedioic acid, hexyl propyl group diester

[4-(cyclopropyl carbonyl) phenyl] amyl group-propanedioic acid, dibutylester

[4-(cyclopropyl carbonyl) phenyl] amyl group-propanedioic acid, butyl amyl group diester

[4-(cyclopropyl carbonyl) phenyl] amyl group-propanedioic acid, butyl hexyl diester

[4-(cyclopropyl carbonyl) phenyl] amyl group-propanedioic acid, diamyl ester

[4-(cyclopropyl carbonyl) phenyl] amyl group-propanedioic acid, hexyl amyl group diester

[4-(cyclopropyl carbonyl) phenyl] amyl group-propanedioic acid, dihexyl

[4-(cyclopropyl carbonyl) phenyl] hexyl-propanedioic acid, diethyl ester

[4-(cyclopropyl carbonyl) phenyl] hexyl-propanedioic acid, dimethyl ester

[4-(cyclopropyl carbonyl) phenyl] hexyl-propanedioic acid, the ethyl-methyl diester

[4-(cyclopropyl carbonyl) phenyl] hexyl-propanedioic acid, the methyl-propyl diester

[4-(cyclopropyl carbonyl) phenyl] hexyl-propanedioic acid, the butyl methyl diester

[4-(cyclopropyl carbonyl) phenyl] hexyl-propanedioic acid, the methyl amyl diester

[4-(cyclopropyl carbonyl) phenyl] hexyl-propanedioic acid, the hexyl methyl diester

[4-(cyclopropyl carbonyl) phenyl] hexyl-propanedioic acid, the ethyl propyl diester

[4-(cyclopropyl carbonyl) phenyl] hexyl-propanedioic acid, the butyl ethyl diester

[4-(cyclopropyl carbonyl) phenyl] hexyl-propanedioic acid, the ethyl pentyl group diester

[4-(cyclopropyl carbonyl) phenyl] hexyl-propanedioic acid, the ethylhexyl diester

[4-(cyclopropyl carbonyl) phenyl] hexyl-propanedioic acid, dipropyl

[4-(cyclopropyl carbonyl) phenyl] hexyl-propanedioic acid, butyl propyl group diester

[4-(cyclopropyl carbonyl) phenyl] hexyl-propanedioic acid, amyl group propyl group diester

[4-(cyclopropyl carbonyl) phenyl] hexyl-propanedioic acid, hexyl propyl group diester

[4-(cyclopropyl carbonyl) phenyl] hexyl-propanedioic acid, dibutylester

[4-(cyclopropyl carbonyl) phenyl] hexyl-propanedioic acid, butyl amyl group diester

[4-(cyclopropyl carbonyl) phenyl] hexyl-propanedioic acid, butyl hexyl diester

[4-(cyclopropyl carbonyl) phenyl] hexyl-propanedioic acid, diamyl ester

[4-(cyclopropyl carbonyl) phenyl] hexyl-propanedioic acid, hexyl amyl group diester

[4-(cyclopropyl carbonyl) phenyl] hexyl-propanedioic acid, dihexyl

Step G:[4-(4-chloro-1-oxygen-butyl) phenyl] preparation of methyl-diethyl malonate

Hydrogen chloride gas is blasted [4-(cyclopropyl carbonyl) phenyl] methyl-diethyl malonate (570mg, in ethanol 2.0mmol) (4mL) solution 5 minutes.With vlil.After 18 hours, solution is cooled to room temperature and blasted nitrogen 1 hour.In residuum, add ethyl acetate and water.Concentrate with the anhydrous magnesium sulfate drying organic phase and with it.Be dissolved in crude product in the ethanol (50mL) and in solution, blasted hydrogen chloride gas 10 minutes.Vlil.Stir after 2 days concentrated solution.In residuum, add ethyl acetate and water.Concentrate with the anhydrous magnesium sulfate drying organic phase and with it.By flash chromatography (150g silica gel, 20% ethyl acetate/heptane is as eluent) purifying, obtain title compound (409mg, 59%).

Step G:[4-(4-chloro-1-oxygen-butyl) phenyl] preparation of methyl-dimethyl malonate

Hydrogen chloride gas is blasted [4-(cyclopropyl carbonyl) phenyl] methyl-dimethyl malonate (315mg, in ethanol 1.1mmol) (3mL)-toluene (9mL) solution 10 minutes.Solution is heated to 68 ℃.After 4 hours, solution is cooled to room temperature and blasted nitrogen 1 hour.In residuum, add ethyl acetate and water.With the anhydrous magnesium sulfate drying organic phase and with its concentrated title compound (321mg, 91%) that obtains.

In addition, the synthesis step of describing by step G can prepare following compounds:

[4-(4-bromo-1-oxygen-butyl) phenyl] methyl-propanedioic acid, diethyl ester

[4-(4-iodo-1-oxygen-butyl) phenyl] methyl-propanedioic acid, diethyl ester

[4-(4-bromo-1-oxygen-butyl) phenyl] methyl-propanedioic acid, dimethyl ester

[4-(4-iodo-1-oxygen-butyl) phenyl] methyl-propanedioic acid, dimethyl ester

In addition, all that in the illustrative example of step F, list from substituting group position change derive and the building-up process preparation described all can be of compound by step G.

Step H:[4-[4-[4-(hydroxyl diphenyl-methyl)-piperidino]-the 1-oxygen-butyl] phenyl] preparation of methyl-diethyl malonate

With [4-(4-chloro-1-oxygen-butyl) phenyl] methyl-diethyl malonate (380mg, 1.1mmol), salt of wormwood (450mg, 3.2mmol), α-(4-pyridyl) diphenyl-carbinol (500mg, 1.9mmol), water (4mL) and toluene (10mL) mixes.Mixture heating up is refluxed.After 7 days, mixture is cooled to room temperature.Add ethyl acetate and water.With salt water washing organic phase, with anhydrous magnesium sulfate drying and concentrated.By flash chromatography (200g silica gel, 10% methyl alcohol/chloroform is as eluent) purifying, obtain title compound (627mg, 99%).

Step H:[4-[4-[4-(hydroxyl diphenyl-methyl)-piperidino]-the 1-oxygen-butyl] phenyl] preparation of methyl-dimethyl malonate

With [4-(4-chloro-1-oxygen-butyl) phenyl] methyl-dimethyl malonate (300mg, 0.92mmol), salt of wormwood (350mg, 2.5mmol), α-(4-pyridyl) diphenyl-carbinol (500mg, 1.9mmol), water (3mL) and toluene (7mL) mixes.Mixture heating up is refluxed.After 5 days, mixture is cooled to room temperature.Add ethyl acetate and water.With salt water washing organic phase, with anhydrous magnesium sulfate drying and concentrated.By flash chromatography (150g silica gel, 10% methyl alcohol/chloroform is as eluent) purifying, obtain title compound (387mg, 76%).

In addition, all that in the illustrative example of step F, list from substituting group position change derive and the building-up process preparation described all can be of compound by step H.

Step I:4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-preparation of α-(methylol)-Alpha-Methyl-Phenylacetic acid ethylester

With [4-[4-[4-(hydroxyl diphenyl-methyl)-piperidino]-1-oxygen-butyl] phenyl] (515mg 0.88mol) is dissolved in the tetrahydrofuran (THF) (5mL) and uses the ice bath cooling solution to methyl-diethyl malonate.A part adding three tert.-butoxy lithium aluminium hydride in 20 minutes (1 molar solution in tetrahydrofuran (THF) of 10mL, 10mmol).After 2 hours, solution is warmed to room temperature.After 48 hours, with the ice bath cooling solution and add 10% aqueous potassium hydrogen sulfate (10mL).With salt water washing organic phase, and use anhydrous magnesium sulfate drying, concentrate.By flash chromatography (150g silica gel, 5% methyl alcohol/chloroform is as eluent) purifying, obtain title compound (321mg, 67%).

In addition, following compounds can prepare by the building-up process of describing among the step I:

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-Alpha-Methyl-toluylic acid, methyl esters

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-Alpha-Methyl-toluylic acid, propyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-Alpha-Methyl-toluylic acid, butyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-Alpha-Methyl-toluylic acid, pentyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-Alpha-Methyl-toluylic acid, own ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-ethyl-toluylic acid, methyl esters

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-ethyl-toluylic acid, ethyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-ethyl-toluylic acid, propyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-ethyl-toluylic acid, butyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-ethyl-toluylic acid, pentyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-ethyl-toluylic acid, own ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-propyl group-toluylic acid, methyl esters

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-propyl group-toluylic acid, ethyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-propyl group-toluylic acid, propyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-propyl group-toluylic acid, butyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-propyl group-toluylic acid, pentyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-propyl group-toluylic acid, own ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-butyl-toluylic acid, methyl esters

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-butyl-toluylic acid, ethyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-butyl-toluylic acid, propyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-butyl-toluylic acid, butyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-butyl-toluylic acid, pentyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-butyl-toluylic acid, own ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-amyl group-methyl phenylacetate

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-amyl group-toluylic acid, ethyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-amyl group-toluylic acid, propyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-amyl group-toluylic acid, butyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-amyl group-toluylic acid, pentyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-amyl group-toluylic acid, own ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-hexyl-toluylic acid, methyl esters

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-hexyl-toluylic acid, ethyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-hexyl-toluylic acid, propyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-hexyl-toluylic acid, butyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-hexyl-toluylic acid, pentyl ester

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-hexyl-toluylic acid, own ester

Step J:4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-preparation of α-(methylol)-Alpha-Methyl-toluylic acid

With 4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-Alpha-Methyl-Phenylacetic acid ethylester (200mg, 0.37mmol) be dissolved in methyl alcohol (8mL) and the tetrahydrofuran (THF) (12mL), add the 1 molar sodium hydroxide aqueous solution of 1.6mL (1.6mmol).After 4 hours, with solution be cooled to room temperature and dropwise add 10% hydrochloric acid (about 1mL) to pH be 5～6.With solution concentration and by flash chromatography (50g silica gel, methyl alcohol/chloroform gradient elution) purifying, obtain title compound (127mg, 66%).

In addition, following compounds can prepare by the building-up process of describing among the step J:

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-ethyl-toluylic acid

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-propyl group-toluylic acid

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-butyl-toluylic acid

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-amyl group-toluylic acid

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-α-hexyl-toluylic acid

The synthetic embodiment that schema B lists

(210g, 1.6mol) the pulpous state liquid in methylene dichloride (200mL) dropwise adds 4-chlorobutanoylchloride (121g) to refrigerative aluminum chloride in ice bath, keeps vessel temp simultaneously and is lower than 10 ℃.After 10 minutes, (118g 0.72mol), keeps vessel temp simultaneously and is lower than 10 ℃ dropwise to add ethylbenzene acetate.Mixture at room temperature stirred 1 hour, then was heated to 40 ℃.After 4 hours, solution is cooled to room temperature and inclines to trash ice (2L).Add methylene dichloride (1L).Separate organic phase.Water is with 2 parts of dichloromethane extractions, every part of 1L.Organic phase drying (the MgSO that merges ₄) and concentrate.Add toluene (1L), and with solution concentration to about 500mL.Add ethanol (500mL).Heated solution to 70 ℃ also blasted HCl (g) 20 minutes.Solution blasts nitrogen and concentrates.By silica gel (2.5L) chromatogram use the ethyl acetate/heptane gradient elution can obtain between 1: 1 mixture (119g) of position, contraposition ethyl (4-chloro-1-oxygen-butyl) toluylic acid.To lithium hydroxide (23.5g, position between adding in the pulpous state liquid of water 0.56mol) (100mL) and ethanol (100mL), 1: 1 mixture of contraposition ethyl (4-chloro-1-oxygen-butyl) toluylic acid (50g, 0.19mol).Exothermic heat of reaction is cooled off with ice bath.After 1 hour, solution is warmed to room temperature.After 18 hours, concentrate mixed solution.Add entry (400mL) and concentrated hydrochloric acid (until pH4).Add ethyl acetate (600mL).Separate organic phase, with salt water washing and dry (MgSO ₄).Solution heats in vapor bath and adds gac (about 3g).Mixture filters and concentrates by Celite.Residuum is dissolved in ethyl acetate (300mL) and heptane (600mL) under heating.Add crystal seed.Have machine oily matter after the cooling.Add heptane (500mL), mixture heating up is refluxed, and handle, filter and adding crystal seed (seeded) with gac (about 5g).Collect solid. ¹H NMR shows that it is contraposition: about 4: 1 mixture of meta-isomer.Recrystallization obtains 4-(cyclopropyl carbonyl) toluylic acid (4.3g, 11%) in ethyl acetate/heptane.

The synthetic embodiment that schema C lists

The preparation of step a:4-(cyclopropyl carbonyl) Phenylacetic acid ethylester

See this paper front schema A, the preparation of describing in the step e

Step b:[4-(cyclopropyl carbonyl)]-preparation of α-alpha-alpha-dimethyl phenyl acetic acid ethyl ester

In 2L glass jacket reactor, add 4-(cyclopropyl carbonyl) Phenylacetic acid ethylester (232g, 1 mole), diglyme (150mL) and methyl chloride (127g, 2.5 moles).At in the additive vessel of heating, pack into potassium tert.-butoxide (182.4g, 1.6 moles) and diglyme (1050mL).Reactor jacket is located at-10 ℃, and the material in the additive vessel is heated to 60 ℃.The internal temperature that reacts with maintenance is lower than 25 ℃ speed adding alkaline solution.After finishing the adding of alkaline solution, the ethanolic soln (86g, 0.3 mole) that adds 21% sodium ethylate is removed excessive methyl chloride.Then, the entire reaction mixture stirs with toluene (900mL) that contains sodium bicarbonate (8.4g) and water (1200mL).The back organic phase that is separated is washed to remove remaining potassium chloride salt with other water (200mL).Then do not need through being separated, whole solution is acidified to pH=3 with concentrated hydrochloric acid.Organic phase has just obtained title compound after removing and desolvating.

The preparation of step c:4-(4-chloro-1-oxygen-butyl)-α-alpha-alpha-dimethyl phenyl acetic acid ethyl ester

In being furnished with airway, overhead stirrer and temperature controlled 4L reactor, add [4-(cyclopropyl carbonyl)]-α-alpha-alpha-dimethyl phenyl acetic acid ethyl ester (500g).Oil is heated to 60 ℃, and head space is found time.Then add HCl, pressure is risen to 10psig.After 4 hours, the HCl that venting is excessive, oil blew 5 minutes with nitrogen.

Steps d: ethyl 4-[4-[4-(hydroxyl trityl)-piperidino]-the 1-oxygen-butyl]-preparation of α-alpha-alpha-dimethyl phenylacetyl chlorination hydrogen

According to people such as Carr at U.S.P.No.4,254, the process of describing in 129,4.5g the ethyl 4-of the α-α of (0.0163 mole)-phenylbenzene-4-piperidine carbinols, 6.1g (0.0205 mole) (4-chloro-1-oxygen-butyl)-α-alpha, alpha-dimethyl phenylacetic acid ester, 5g (0.05 mole) saleratus and the mixture stirring and refluxing of 0.05g potassiumiodide in 50mL toluene 72 hours are then filtered.Then in filtrate, add ether and gasiform hydrogenchloride, collect the throw out that generates and in methyl alcohol-butanone and butanone recrystallization repeatedly, obtain ethyl 4-[4-[4-(hydroxyl diphenyl-methyl)-piperidino]-the 1-oxygen-butyl]-α-alpha-alpha-dimethyl phenylacetyl chlorination hydrogen.M.P.205.5°～208℃。

Step e: ethyl 4-[4[4-(hydroxyl diphenyl-methyl)-piperidino]-1-hydroxyl butyl]-preparation of α-alpha-alpha-dimethyl phenyl acetic acid ester

According to people such as Carr at U.S.P.No.4,254, the process of describing in 129, the ethyl 4-[4-[4-of (5.64g 0.01 mole) (hydroxyl diphenyl-methyl)-piperidino]-the 1-oxygen-butyl]-the 200mL dehydrated alcohol of α-alpha-alpha-dimethyl phenylacetyl chlorination hydrogen and 0.5g platinum oxide and 50mL methanol solution about 1 hour in about 50psi hydrogenation, there is not keto carbonyl group function group to exist until infrared demonstration.Filtering solution, filtrate concentrates, residuum recrystallization in butanone and methyl alcohol-butanone obtains ethyl 4-[4-[4-(hydroxyl diphenyl-methyl)-piperidino]-1-hydroxyl butyl]-α-alpha-alpha-dimethyl phenylacetyl chlorination hydrogen, M.P.185 °～187 ℃.

Step f:4-[4[4-(hydroxyl diphenyl-methyl)-piperidino]-1-hydroxyl butyl]-α-alpha-alpha-dimethyl phenyl acetic acid

According to people such as Carr at U.S.P.No.4,254, the process of describing in 129 is to 0.6g ethyl 4-[4[4-(hydroxyl diphenyl-methyl)-piperidino]-1-hydroxyl butyl]-add the sodium hydroxide solution of 10mL 50% in the 20mL straight alcohol solution of α-alpha-alpha-dimethyl phenyl acetic acid ester.Mixture refluxed 3.5 hours and was condensed into solid, added minimum methyl alcohol again with the dissolving residuum.The hydrochloric acid soln of adding 10% reaches 7 until pH, removes methyl alcohol and adds entry (25mL) by evaporation.The throw out recrystallization in the methyl alcohol butanone that generates obtains 4-[4[4-(hydroxyl diphenyl-methyl)-piperidino]-1-hydroxyl butyl]-α-alpha-alpha-dimethyl phenyl acetic acid, M.P.195 °～197 ℃.

According to the present invention, molecular formula is used as histamine H as the piperidine derivative of (I) ₁-receptor antagonist alleviates patient's the symptom of the allergic disorder of histamine-mediated.The allergic disorder of histamine-mediated is disease or the state with allergy factor of histamine-mediated, as seasonal rhinallergosis, repeatability rhinitis, spontaneous nettle disease, asthma etc.Treat the allergic disorder sx according to the present invention, refer to and compare when not treating, the severity of symptom reduces, and might not show that disease thoroughly eliminates.

The antihistamine potentiality by test-compound with and the animal meninx in H ₁The antagonism composition of-Histamine Receptors link to each other [ ³H] pyrrole receives the avidity of bright (pyrilamine) binding site and measures.Can represent test-compound and maincenter and periphery H to the avidity of this acceptor ₁The interactional potentiality of-Histamine Receptors.

Below method be used for measuring in test-compound and the rat cortex [ ³H] pyrrole receives the avidity of bright binding site.

Take out male rat cerebral tissue childhood.Dissect cortex and be stored in-20 ℃ or use at once.Be organized in the ice-cold 50nM K/NaPO of 10mL ₄Damping fluid (pH7.4) is middle with Polytron (being provided with 6,15 minutes) homogenate.Homogenate 4 ℃ in 40, under the 000g centrifugal 15 minutes.Throw out in same damping fluid resuspending to obtain 100mg weight in wet base/mL damping fluid.Contain 50mM K/NaPO in the culture tube ₄Damping fluid, promethazine (final concentration is 2.10-6M) or test-compound, ³The H pyrrole is received bright (final concentration is 2nM) and homogenate (every pipe 10mg weight in wet base), liquor capacity is 250～1000mL in the pipe at last.Cultivate after 30 minutes under the room temperature, stop cultivating by filtering fast with Whatman GF/B glass fibre filter, this strainer water preimpregnation when with the Brandel cell harvestor, maybe when filtering with 96 hole Skareon cell harvestors, this strainer is without water preimpregnation.Strainer is with 3 * 3mL 0.9%NaCl (Brandel) drip washing or with 10 seconds of the pre-wetting and drip washing of NaCl (Skatron).Strainer or be transferred in the scintillation vial and add 10mL Quicksafe A to be used for liquid-scintillation spectrometry perhaps melts to the solid scintillator thin layer on the strainer, and strainer is then with β plate (betaplate) β rolling counters forward. ³The H pyrrole is received bright specificity in conjunction with measuring by the amount that exceeds the blank value when having 2.10～6M promethazine.The protein content of film is by the method for Lowry etc., J.Biol.Chem.193, and 265～275 (1951) measure.(GraphPadSoftware Inc.) or similar programanalysis displacement curve, obtains Hill slope and IC by utilization GraphPad ₅₀Value.K _iAt Biochem.Pharmacol., use to obtain from the saturation experiments that carry out under the same conditions the front by the Cheng-Prusoff formula described in 22,3099～3108 (1973) by Cheng etc. for value ³The H pyrrole is received bright K _DValue is calculated.

4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-K of α-(methylol)-Alpha-Methyl-toluylic acid _iBe 3.6 * 10 ^-7, show that molecular formula can be used for treating the allergic disorder of histamine-mediated as the piperidine derivative of (I).

Term used herein " patient " refers to the grownup of the allergic disorder of suffering from histamine-mediated.For realizing purpose of the present invention, term " grownup " referred to 12 years old or above people, can use usually and recommend to be used for the allergic disorder that adult antihistamine dosage is treated him.

Determine which patient will benefit from the present invention, fully in those skilled in the art's ability and ken.By Clinical Laboratory, physical examination and medical treatment/family history, the clinicist of this area is easy to definite those and suffers from the patient of the allergic disorder of histamine-mediated.

The consumption of new compound will change according to application method, can be effective arbitrarily antianaphylaxis amount.The consumption of new compound can in very large range change, and provides the significant quantity of about 0.01 to 20mg/kg patient body weight every day with unit dosage form, thereby obtains expected effect.Such as, the antihistamine of expection, anti-allergy and bronchodilator effect can by give patient every day with about 10mg extremely the molecular formula of about 50mg obtain as the piperidine derivative of (I).Preferably every day, dosage was that about 20mg is to about 40mg.Most preferred every day, dosage was about 30mg.

Be appreciated that every day, dosage can be used to patient with the scheme of single dose or multiple doses.For example, one day dosage can be with once, and the form of twice, three time or four times dosage is used.Usually, these unitary doses are equicohesive, and they will arrange to take by the regular hour, thereby the timed interval of at every turn taking was almost equated in one day.For example, the mode of taking once a day is to take 1 time in per approximately 24 hours; The semidiurnal mode of taking is to take 1 time in per approximately 12 hours; One day three times the mode of taking is to take once in per approximately 8 hours; One day four times the mode of taking is to take once in per approximately 6 hours.

According to the present invention, under the prerequisite of the significant quantity that guarantees biological utilisation, molecular formula can be in any form as the piperidine derivative of (I) or the mode administration, comprises oral or the parenteral approach.For example, molecular formula as the piperidine derivative of (I) can be oral, subcutaneous, administration such as in skin, nose.Oral administration preferably.The technician of formulation art can be at an easy rate according to the state of the characteristic of selected compounds, the disease that will treat, the stage and the suitable form of medication and the mode of other conditions associated selection of disease.

This compound can be individually dosed, and perhaps with pharmaceutically acceptable carrier or the vehicle form administration with pharmaceutical composition, the ratio of carrier or vehicle and character are determined according to the pharmacy convention of selected route of administration and standard.Though molecular formula is effective as the piperidine derivative itself of (I), in order to realize stablizing, make things convenient for purposes such as crystallization, raising solubleness, it can be with the form prescription and the administration of the acceptable acid-adducting salt of pharmacy.In addition, molecular formula is as the independent polymorphic form of the piperidine derivative of (I), solvate or independent steric isomer [i.e. (R, R)-and 4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-Alpha-Methyl-toluylic acid, (R, S)-and 4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-Alpha-Methyl-toluylic acid, (S, S)-4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-Alpha-Methyl-toluylic acid and (S, R)-4-[1-hydroxyl-4-[4-(hydroxyl diphenyl-methyl)-piperidino] butyl]-α-(methylol)-Alpha-Methyl-toluylic acid] can be used.

The present invention has comprised and has comprised piperidine derivative and the mixture of one or more inert supports or the composition of binding substances of molecular formula as (I).These compositions can be used as, for example, and the convenient means of analytical standard, bulk shipment (convenient means of making bulkshipments), perhaps pharmaceutical composition.Molecular formula as (I) but the amount of analysis of piperidine derivative refer to the amount that the standard analyzer being familiar with and knowing with those skilled in the art and technology can easily be measured.Molecular formula as (I) but the amount of analysis of piperidine derivative be generally about 0.001% to about 75% of composition weight.Inert support can be do not degrade or not with any material of molecular formula as the piperidine derivative covalent reaction of (I).The example of suitable inert support be water, water-containing buffering liquid as be used for the water-containing buffering liquid of organic solvent that high performance liquid chromatography (HPLC) analyzes such as acetonitrile, ethyl acetate, hexane etc. and pharmaceutically acceptable carrier or vehicle.

Unique more is, the present invention has comprised a kind of pharmaceutical composition of solid unit dosage form, it comprise about 15mg extremely the molecular formula of about 30mg as the piperidine derivative of (I) and the mixture of pharmaceutically acceptable carrier.Term used herein " solid unit dosage form " has comprised solid dosage such as tablet, the capsule etc. that are used for oral administration, also comprised the solid dosage that is used for the enteron aisle external administration as through the eye path through skin medicine subsides etc.

This pharmaceutical composition prepares in the mode of knowing in the pharmaceutical field.Carrier or vehicle can be can be as the carrier of activeconstituents or solid, semisolid or the fluent material of medium.Appropriate carriers or vehicle are known in the art.Pharmaceutical composition can be used for oral or the enteron aisle external administration, can be with tablet, capsule, solution, suspensoid, through form administrations such as skin medicine subsides.

Molecular formula can be oral as the piperidine derivative of (I), as mixing with an inert thinner or edible carrier.It can be encapsulated in the gelatine capsule or be pressed into tablet.For oral therapeutic administration, molecular formula can be with mixed with excipients and with tablet, capsule, elixir, suspensoid, syrup as the piperidine derivative of (I), and glutinous rice charta (wafers), gum forms such as (chewing gums) are used.It is activeconstituents that these preparations should contain at least 4% compound of the present invention, but according to specific form can unit weight about 4% to about 70% variation.The amount of the compound that exists in the composition should make dosage suitable.According to the present invention, preferred compositions and preparation are to contain about 15mg and prepare to the amount of about 30mg to satisfy oral unit dosage form.Most preferred oral dosage is the dosage that contains the 15mg to 30mg that has an appointment.

Tablet, pill, capsule etc. also can contain one or more following auxiliary materials: tackiness agent such as Microcrystalline Cellulose, tragacanth gum or gelatin, excipient such as starch or lactose, disintegrating agent such as Lalgine, Primogel ^TM, W-Gum, carbonate such as sodium bicarbonate or lime carbonate etc., lubricant such as Magnesium Stearate or Sterotex ^TM, glidant such as colloid silica, sweeting agent such as sucrose or asccharin can be added into, or add correctives such as peppermint, wintergreen oil or orange seasonings.When preparation is capsule, except the material that contains the above-mentioned type, can also contain liquid carrier such as polyoxyethylene glycol or fatty oil.Other formulation can contain other various materials in order to modification preparation physical form, for example dressing.Thereby tablet or pill can be with sugar, shellac or other enteric coating agents dressings.Syrup also can contain sucrose, some sanitas, dyestuff, pigment and correctives as sweeting agent except containing existing compound.The material that is used to prepare these compositions must be pharmaceutical purity and be nontoxic in usage quantity.Preferred vehicle is W-Gum, gelatin, lactose, Magnesium Stearate and sodium bicarbonate.

Oral unit dosage form can be made the prescription of quick-release or slowly-releasing.These forms can be according to traditional technology and process prescription, thereby obtains needed solubleness and bioavailability.

In addition, molecular formula can be made into solution or suspension agent as the piperidine derivative of (I), is used for oral or the enteron aisle external administration.These preparations should contain the molecular formula that accounts for its weight at least 0.1% piperidine derivative as (I), but also can change to about 50% scope 0.1.Molecular formula in such composition should make oral as the amount of the piperidine derivative of (I) or the enteron aisle external administration after obtain suitable dosage.

Solution or suspensoid also can comprise one or more following auxiliary materials: sterile diluent such as water for injection, salts solution, fixed oil, polyoxyethylene glycol, glycerine, propylene glycol or other synthetic, antiseptic-germicide such as phenylcarbinol or methyl p-hydroxybenzoate, antioxidant such as xitix or sodium bisulfite, sequestrant such as ethylenediamine tetraacetic acid (EDTA), buffering salt such as acetate, Citrate trianion or phosphoric acid salt, and the reagent of adjustment of tonicity such as sodium-chlor or glucose.

Molecular formula is as the conventional art preparation of knowing in the skin formulation can be by pharmaceutical field of the piperidine derivative of (I), as by molecular formula is sneaked in the various polymerization depot matrix materials (polymeric reservoir matrix materials) as the piperidine derivative of (I).Can comprise pressure-sensitive vinylformic acid, silicone, polyurethane(s), ethylene vinyl acetate copolymer, polyolefine in these polymerization depot matrix materials, and rubber adhesion matrix, medical grade silicone fluid and medical grade silicone elastomer, these materials of this area are common formation medicine is carried depots through skin materials.

Will also be understood that be molecular formula of the present invention as the piperidine derivative of (I) can with multiple normal and activeconstituents prescription that antihistaminic share, comprise pseudo-ephedrine etc. as decongestant, anodyne such as Paracetamol etc., NSAID (non-steroidal anti-inflammatory drug) such as Ibuprofen BP/EP etc.

Claims

1. A compound of the formula,

in

R ₁ is H or C ₁ ~ C ₆ alkyl, and the C ₁ ~ C ₆ alkyl part is straight chain or branched;

R ₂ is -COOH or -COO alkyl, the alkyl part of which has 1 to 6 carbon atoms, and is straight or branched; or its stereoisomer or pharmaceutically acceptable acid addition salt.

2. The compound of claim 1, wherein R ₁ is methyl and R ₂ is COOCH ₂ CH ₃ .

3. A compound of the formula,

in

R ₂ and R ₃ independently represent a C ₁ -C ₆ alkyl group, wherein the C ₁ -C ₆ alkyl portion is linear or branched; or a stereoisomer thereof.

4. The compound as claimed in claim 3, wherein R ₁ is methyl, R ₂ and R ₃ are ethyl.

5. A compound of the formula,

in

R ₂ and R ₃ independently represent C ₁ -C ₆ alkyl, and the C ₁ -C ₆ alkyl part is straight chain or branched;

X is Cl, Br, or I; or a stereoisomer thereof.

6. The compound of claim 5, wherein X is Cl, R ₁ is methyl, R ₂ and R ₃ are ethyl.

7. A compound of the formula, in

R ₂ and R ₃ independently represent a C ₁ -C ₆ alkyl group, and the C ₁ -C ₆ alkyl moiety is linear or branched; or a stereoisomer or a pharmaceutically acceptable acid addition salt thereof.

8. The compound as claimed in claim 7, wherein R ₁ is methyl, R ₂ and R ₃ are ethyl.

9. A compound of the formula, in

X is Cl, Br or I.

10. The compound of claim 9, wherein X is Cl.

11. A process for preparing a compound of the formula,

in

R ₂ is -COOH or -COO alkyl, the alkyl part of which has 1 to 6 carbon atoms, and is straight or branched; or its stereoisomer or pharmaceutically acceptable acid addition salt, the method Include the following steps:

(a) with a compound of the formula, in

R ₂ and R ₃ independently represent C ₁ -C ₆ alkyl, and the C ₁ -C ₆ alkyl part is straight chain or branched; or

Its stereoisomers react with suitable hydrogen halides to generate [4-(4-halogenated 1-oxo-butyl)phenyl]malonic acid diesters of the following molecular formula,

in

X is Cl, Br or I; or a stereoisomer thereof;

(b) reacting the [4-(4-halo-1-oxo-butyl)phenyl]malonate diester with a compound of the formula,

Generate [4-[4-[4-(hydroxybenzhydryl)-1-piperidinyl]-1-oxobutyl]phenyl]malonate diester compound of the following molecular formula,

in

R ₂ and R ₃ independently represent C ₁ -C ₆ alkyl, and the C ₁ -C ₆ alkyl part is straight or branched; or its stereoisomer or pharmaceutically acceptable acid addition salt;

(c) the [4-[4-[4-(hydroxybenzhydryl)-1-piperidinyl]-1-oxobutyl]phenyl]malonate diester compound with an appropriate selective reduction react with reagents to generate 4-[1-hydroxyl-4-[4-(hydroxybenzhydryl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-phenylacetate compound with the following molecular formula ,

in

R ₂ is -COO alkyl, the alkyl part of which has 1 to 6 carbon atoms, and is straight or branched; or its stereoisomer or pharmaceutically acceptable acid addition salt;

(d) optionally p-4-[1-hydroxy-4-[4-(hydroxybenzhydryl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-phenylacetate compound Hydrolysis is carried out to generate compounds of the following molecular formula, in

_R2 is -COOH, or a stereoisomer or a pharmaceutically acceptable acid addition salt thereof; provided that the keto group in each of the compounds described in steps a to b is optionally protected or unprotected.

12. The method of claim 11, wherein the suitable selective reducing agent is lithium aluminum hydride tri-tert-butoxy.

13. The method of claim 11, wherein the method is catalyzed.

14. The method according to claim 11, wherein the suitable selective reducing agent is a suitable silane in combination with a suitable titanocene-based catalyst.

15. The method of claim 14, wherein the suitable silane is polymethylhydrosilane and the suitable titanocene-based catalyst is " _Cp2TiH ".

16. The method of claim 11, wherein the reduction reaction is asymmetric.

17. A method of treating a patient with a histamine-mediated allergic disorder, comprising daily administering to said patient an antiallergic effective amount of a compound as claimed in claim 1.

18. A pharmaceutical composition in unit dosage form, comprising a mixture of an effective antiallergic amount of the compound as claimed in claim 1 and a pharmaceutically acceptable carrier.

19. A process for preparing a compound of the formula,

in

R ₁ is a C ₁ -C ₆ alkyl group, and the C ₁ -C ₆ alkyl part is straight or branched, and the method includes the following steps:

(a) with a phenylacetate of the formula,

in

R ₁ is C ₁ ~ C ₆ alkyl, and its C ₁ ~ C ₆ alkyl part is straight chain or branched, and it reacts with 4-halogen substituted butyryl halide under Friedel-Crafts conditions to generate para-position with the following molecular formula and mixtures of meta-substituted ω-halo-α-keto-phenylacetates,

in

_R is the same as previously defined herein, X is Cl, Br or I;

(b) hydrolyzing the mixture of para- and meta-substituted ω-halo-α-keto-phenylacetic acid esters to generate a mixture of para- and meta-substituted (cyclopropylcarbonyl) phenylacetic acid with the following molecular formula

(c) selectively crystallizing and isolating substantially pure 4-(cyclopropylcarbonyl)phenylacetic acid.

20. The method of claim 19, wherein X is Cl.

twenty one. The method according to claim 19, comprising steps (a), (b) and (c) of claim 19, and further comprising:

(d) esterification of substantially pure 4-(cyclopropylcarbonyl)phenylacetate to form the corresponding 4-(cyclopropylcarbonyl)phenylacetate of the formula, Wherein R ₁ is C ₁ ~ C ₆ alkyl, and its C ₁ ~ C ₆ alkyl part is straight chain or branched;

(e) alkylating the 4-(cyclopropylcarbonyl)phenylacetate with a suitable alkylating agent to produce the corresponding alkylated [4-(cyclopropylcarbonyl)phenyl]phenylacetate,

in

R ₁ is the same as defined above herein, R ₂ and R ₃ independently represent C ₁ -C ₆ alkyl, and the C ₁ -C ₆ alkyl part is straight chain or branched;

(f) ring-opening the alkylated [4-(cyclopropylcarbonyl)phenyl]phenyl acetate to generate the corresponding [4-(4-halo-1-oxo-butyl)benzene with the following molecular formula base] phenylacetate,

wherein R ₁ , R ₂ and R ₃ are the same as previously defined herein, and X is Cl, Br or I;

(g) reacting alkylated [4-(4-halo-1-oxo-butyl)phenyl]phenylacetate with a compound of the formula,

[4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]phenyl]phenylacetate of the formula,

in

R ₁ , R ₂ and R ₃ are the same as previously defined herein; or stereoisomers or pharmaceutically acceptable acid addition salts thereof;

(h) react [4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]phenyl]phenylacetate with a suitable reducing agent to produce 4-[1-Hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]phenylacetate of the formula,

in

(i) optionally hydrolyzing 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]phenylacetate to produce a compound of the formula,

in

R _and _R are the same as previously defined herein; or stereoisomers or pharmaceutically acceptable acid addition salts thereof; provided that the keto group of each of the compounds described in steps d to g is optionally protected or unprotected.

twenty two. The method according to claim 21, wherein in the compound generated in step (i), R ₂ and R ₃ are methyl.

twenty three. The method according to claim 19, comprising steps (a), (b) and (c) of claim 19, and further comprising:

(d) pure 4-(cyclopropylcarbonyl) phenylacetate is esterified to generate the corresponding molecular formula of 4-(cyclopropylcarbonyl) phenylacetate,

in

R ₁ is C ₁ ~ C ₆ alkyl, and the C ₁ ~ C ₆ alkyl part is straight chain or branched;

(e) acylation of (cyclopropylcarbonyl) phenylacetate to generate [4-(cyclopropylcarbonyl) phenyl] malonate diester of the following molecular formula:

in

_R2 is H;

R ₁ and R ₃ independently represent C ₁ -C ₆ alkyl, and the C ₁ -C ₆ alkyl part is straight chain or branched;

(f) optionally alkylating [4-(cyclopropylcarbonyl)phenyl]malonate diester to generate [4-(cyclopropylcarbonyl)phenyl]malonate diester of the following molecular formula,

in

R ₂ is C ₁ ~ C ₆ alkyl, and its C ₁ ~ C ₆ alkyl part is linear or branched; R ₁ and R ₃ independently represent C ₁ ~ C ₆ alkyl, and its C ₁ ~ C ₆ alkyl The base moiety is linear or branched;

(g) Diester of [4-(cyclopropylcarbonyl)phenyl]malonate,

in

R ₂ is H or C ₁ -C ₆ alkyl, and the C ₁ -C ₆ alkyl part is straight chain or branched;

R ₁ and R ₃ independently represent a C ₁ ~C ₆ alkyl group, and the C ₁ ~C ₆ alkyl part is a straight chain or a branched chain, which reacts with an appropriate hydrogen halide to generate [4-(4-halogen Substituted-1-oxo-butyl)phenyl]malonic acid diester,

in

X is Cl, Br or I; or a stereoisomer thereof;

(h) reacting [4-(4-halo-1-oxo-butyl)phenyl]malonate diester with a compound of the formula, [4-[4-[4-(hydroxybenzhydryl)-1-piperidinyl]-1-oxobutyl]phenyl]malonate diester of the molecular formula is generated, in

R ₁ and R ₃ independently represent C ₁ -C ₆ alkyl, and the C ₁ -C ₆ alkyl part is straight or branched; or its stereoisomer or pharmaceutically acceptable acid addition salt;

(i) [4-[4-[4-(hydroxybenzhydryl)-1-piperidinyl]-1-oxobutyl]phenyl]malonic acid diester compound and a suitable selective reducing agent Reaction generates 4-[1-hydroxyl-4-[4-(hydroxybenzhydryl)-1-piperidinyl] butyl]-alpha-(hydroxymethyl)-phenylacetate compound of the following molecular formula, in

R ₁ is -COO alkyl, the alkyl part of which has 1 to 6 carbon atoms, and is straight or branched; or its stereoisomer or pharmaceutically acceptable acid addition salt;

(j) optionally 4-[1-hydroxy-4-[4-(hydroxybenzhydryl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-phenylacetate compound Hydrolysis is carried out to generate compounds of the following molecular formula,

in

R ₁ is -COOH; or a stereoisomer or a pharmaceutically acceptable acid addition salt thereof; provided that the keto group in each of the compounds described in steps d to h is optionally protected or unprotected.

twenty four. The method according to claim 23, wherein R2 in the compound generated by (j) is methyl.

25． A process for preparing a compound of the formula,

Wherein X is Cl, Br or I; The method comprises the following steps:

(a) Compounds with the following molecular formula React with 4-halogen-substituted butyryl halide under Friedel-Crafts conditions to generate para- and meta-substituted (4-halo-1-oxobutyl)-N-methoxy-N- Mixture of methyl-phenylacetamides,

in

X is Cl, Br or I;

(b) selectively crystallizing and isolating substantially pure [4-(4-halo-1-oxobutyl)]-N-methoxy-N-methyl-phenylacetamide of the formula, in

X is Cl, Br or I.

26． The method of claim 25, wherein the 4-halo-substituted butyryl halide is 4-chlorobutyryl chloride.

27． The method according to claim 25, wherein [4-(4-halo-1-oxobutyl)]-N-methoxy-N-methyl-phenylacetamide is [4-(4-chloro -1-Oxobutyl)]-N-methoxy-N-methyl-phenylacetamide.

28． The method according to claim 25, comprising steps (a) and (b) of claim 25, and further comprising:

(c) Hydrolyzing pure [4-(4-halo-1-oxobutyl)]-N-methoxy-N-methyl-phenylacetamide to generate (cyclopropylcarbonyl)benzene with the following molecular formula Acetic acid

(d) esterifying (cyclopropylcarbonyl) phenylacetate to generate (cyclopropylcarbonyl) phenylacetate of the following molecular formula,

in

(e) acylation of (cyclopropylcarbonyl) phenylacetate to generate [4-(cyclopropylcarbonyl) phenyl] malonate diester of the following molecular formula,

in

_R1 is H;

(f) optionally alkylating [4-(cyclopropylcarbonyl)phenyl]malonate diester to produce [4-(cyclopropylcarbonyl)phenyl]malonate diester of the formula,

in

R ₁ is C ₁ ~ C ₆ alkyl, and its C ₁ ~ C ₆ alkyl part is linear or branched, R ₂ and R ₃ independently represent C ₁ ~ C ₆ alkyl, and its C ₁ ~ C ₆ alkyl The base moiety is linear or branched;

(g) [4-(cyclopropylcarbonyl) phenyl] malonate diester with the following molecular formula, in

R ₁ is H or C ₁ ~ C ₆ alkyl, and its C ₁ ~ C ₆ alkyl part is straight chain or branched,

R ₂ and R ₃ independently represent a C ₁ ~C ₆ alkyl group, and the C ₁ ~C ₆ alkyl part is a straight chain or a branched chain, which reacts with an appropriate hydrogen halide to generate [4-(4-halogen Substituted-1-oxo-butyl)phenyl]malonic acid diester,

in

X is Cl, Br or I;

(h) reacting [4-(4-halo-1-oxo-butyl)phenyl]malonate diester with a compound of the formula, Generate [4-[4-[4-(hydroxybenzhydryl)-1-piperidinyl]-1-oxobutyl]phenyl]malonate diester compound of the following molecular formula, in

in

_R2 is -COOH; or a stereoisomer or a pharmaceutically acceptable acid addition salt thereof; provided that the keto group in each of the compounds described in steps c-h is optionally protected or deprotected.

29． The method according to claim 28, wherein [4-(4-halo-1-oxobutyl)]-N-methoxy-N-methyl-phenylacetamide in (c) step is [4 -(4-Chloro-1-oxobutyl)]-N-methoxy-N-methyl-phenylacetamide.

30． The method according to claim 28, wherein in the compound generated in (j) step, R is _methyl .

31． The method according to claim 25, comprising steps (a) and (b) of claim 25, and further comprising:

(c) Hydrolysis of substantially pure [4-(4-halo-1-oxobutyl)]-N-methoxy-N-methyl-phenylacetamide yields (cyclopropylcarbonyl ) phenylacetic acid;

(d) 4-(cyclopropylcarbonyl) phenylacetate is esterified to generate the corresponding molecular formula of 4-(cyclopropylcarbonyl) phenylacetate,

in

(e) Alkylation of 4-(cyclopropylcarbonyl)phenylacetic acid ester with an appropriate alkylating agent to generate the corresponding alkylated [4-(cyclopropylcarbonyl)phenyl]phenylacetic acid of the following molecular formula ester,

in

R ₁ is the same as defined above herein, R ₂ and R ₃ independently represent C ₁ -C ₆ alkyl,

Its C ₁ -C ₆ alkyl moiety is straight chain or branched;

in

R ₁ , R ₂ and R ₃ are the same as previously defined herein; X is Cl, Br or I;

(g) reacting alkylated [4-(4-halo-1-oxo-butyl)phenyl]phenylacetate with a compound of the formula, [4-[4-[4-(hydroxybenzhydryl)-1-piperidinyl]-1-oxobutyl]phenyl]phenylacetate of the formula,

Wherein, R ₁ , R ₂ and R ₃ are the same as defined above; or their stereoisomers or pharmaceutically acceptable acid addition salts;

(h) Reaction of [4-[4-[4-(hydroxybenzhydryl)-1-piperidinyl]-1-oxobutyl]phenyl]phenylacetate with an appropriate reducing agent produces the molecular formula 4-[1-Hydroxy-4-[4-(hydroxybenzhydryl)-1-piperidinyl]butyl]phenylacetate as follows,

in

(i) optionally hydrolyzing 4-[1-hydroxy-4-[4-(hydroxybenzhydryl)-1-piperidinyl]butyl]phenylacetate to produce a compound of the formula,

in

R ₂ and R ₃ are the same as previously defined herein; or their stereoisomers or pharmaceutically acceptable acid addition salts; provided that the keto group in each of the compounds described in steps c to g is optionally replaced by Protected or not protected.

32． The method according to claim 31, wherein [4-(4-halogeno-1-oxobutyl)]-N-methoxy-N-methyl-phenylacetamide in (c) step is [4- (4-Chloro-1-oxobutyl)]-N-methoxy-N-methyl-phenylacetamide.

33． The method according to claim 21, wherein in the compound generated in (h) step, R ₂ and R ₃ are methyl.

34． In one method of synthesizing a compound of the formula,

in

_R2 is -COOH or -COO alkyl, the alkyl part of which has 1 to 6 carbon atoms, and is straight or branched; or its stereoisomers or pharmaceutically acceptable acid addition salts, using the molecular formula as follows compounds as intermediates,

in

X is Cl, Br or I; Its improvement is that the preparation method of described intermediate compound comprises:

(a) Compounds with the following molecular formula

React with 4-halogen substituted butyryl halide under Friedel-Crafts conditions to generate para- and meta-substituted (4-halo-1-oxobutyl)-N-methoxy-N-methyl base-phenylacetamide mixture,

in

X is Cl, Br or I;

(b) selective crystallization and isolation of pure [4-(4-halo-1-oxobutyl)]-N-methoxy-N-methylphenylacetamide of the formula,

in

X is Cl, Br or I.

35． The method of claim 34, wherein the 4-halo-substituted butyryl halide is 4-chlorobutyryl chloride.

36． The method according to claim 34, wherein [4-(4-halo-1-oxobutyl)]-N-methoxy-N-methylphenylacetamide in (b) step is [4- (4-Chloro-1-oxobutyl)]-N-methoxy-N-methylphenylacetamide.

37． In one method of synthesizing a compound of the formula,

in

R ₂ and R ₃ independently represent C ₁ ~ C ₆ alkyl, and the C ₁ ~ C ₆ alkyl part is straight or branched; or its stereoisomer or pharmaceutically acceptable acid addition salt, using the molecular formula The following compounds are used as intermediates,

in

(a) Compounds with the following molecular formula React with 4-halogen substituted butyryl halide under Firedel-Crafts conditions to generate para- and meta-substituted (4-halo-1-oxobutyl)-N-methoxy-N-methyl base-phenylacetamide mixture,

in

X is Cl, Br or I;

(b) selectively crystallize and isolate substantially pure [4-(4-halo-1-oxobutyl)]-N-methoxy-N-methylphenylacetamide of the formula

38． The method of claim 37, wherein the 4-halo-substituted butyryl halide is 4-chlorobutyryl chloride.

39． The method according to claim 37, wherein [4-(4-halo-1-oxobutyl)]-N-methoxy-N-methylphenylacetamide is [4-(4-chloro- 1-Oxobutyl)]-N-methoxy-N-methylphenylacetamide.

40． The method according to claim 37, wherein _R2 and _R3 are methyl groups, and _R1 is a hydrogen atom.

41． In one method of synthesizing a compound of the formula,

in

_R is COOH or COOalkyl, the alkyl portion of which has 1 to 6 carbon atoms, and

is a straight chain or branched chain; or a stereoisomer or a pharmaceutically acceptable acid addition salt thereof, using a carboxylic acid of the following molecular formula as an intermediate, Its improvement is that the preparation method of described carboxylic acid comprises:

(a) phenylacetate of the following molecular formula,

in

R ₁ is C ₁ ~ C ₆ alkyl, and its C ₁ ~ C ₆ alkyl part is straight chain or branched, reacting with 4-halogen substituted butyryl halide under Firedel-Crafts conditions to generate para-position with the following molecular formula and meta-substituted ω-halo-α-keto-phenylacetate mixtures,

Wherein, _R is the same as previously defined herein, and X is Cl, Br or I;

(b) hydrolyzing the para- and meta-substituted ω-halo-α-keto-substituted phenylacetic acid ester mixtures to generate a para- and meta-substituted (cyclopropylcarbonyl) phenylacetic acid mixture with the following molecular formula;

(c) Selective crystallization and isolation of substantially pure 4-(cyclopropylcarbonyl)phenylacetic acid.

42． The method of claim 41, wherein the 4-halo-substituted butyryl halide is 4-chlorobutyryl chloride.

43． The method of claim 41, wherein X is Cl.

44． In one method of synthesizing a compound of the formula,

in

R ₂ and R ₃ independently represent C ₁ ~ C ₆ alkyl, and the C ₁ ~ C ₆ alkyl part is straight or branched; or its stereoisomer or pharmaceutically acceptable acid addition salt, using the molecular formula The following carboxylic acids are used as intermediates,

Its improvement is that the preparation method of described carboxylic acid comprises:

(a) phenylacetate of the following molecular formula,

Wherein R ₁ is C ₁ ~ C ₆ alkyl, and its C ₁ ~ C ₆ alkyl part is straight chain or branched, reacts with 4-halogen substituted butyryl halide under Friedel-Crafts conditions to generate the following molecular formula Omega- and meta-substituted omega-halo-alpha-keto-phenylacetate mixtures,

in

_R is the same as previously defined herein, X is Cl, Br or I;

45． The method according to claim 44, wherein R ₁ is a hydrogen atom, and R ₂ and R ₃ are methyl groups.

46． The method of claim 44, wherein the 4-halogen-substituted butyryl halide is 4-chlorobutyryl chloride.

47． The method of claim 44, wherein X is Cl.

48． Use of the compound described in claim 1 in the preparation of medicines for treating allergic disorders mediated by histamine.